KR830000526B1 - Process for preparing etomidate - containing injection - Google Patents

Abstract

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Description

Method for preparing injection containing etomidate

The present invention relates to a process for the preparation of an injection containing an improved etomidate suitable for intravenous administration.

Ethomidate, represented by R-(+) ethyl1- (1-phenylethyl) -1H-imidazole-5-carboxylate, is alkyl-1- (1-phenylalkyl)-as described in US Pat. No. 3,354,173. It is a short acting hypnotic that belongs to the class of 1H-imidazole-5-carboxylate. More detailed data relating to the hypnosis of ethomidate is described in Arzneimittel-Forschung (Drug Research) 21, 1234 (1971).

Ethomidate has recently been found to be useful as a persistent anesthetic that can be used as a substitute for traditional inhalation anesthesia such as nitrous acid, halotan and the like.

A report on this use is given by Acta anaesth belg. 28 107 (1977) and ibid, 115 (1977), which may be repeated over a period of time to maintain an effective level of drug in the patient's blood when etomidate is used as a continuous anesthetic in terms of short duration anesthetics. Or continuously. This object can be achieved by administering etomidate in the form of an intravenous infusion in a predetermined amount.

One major problem encountered in this development process is finding a suitable pharmaceutical composition that can be used for this purpose. Such compositions must be suitable for special ie intravenous administration and the compositions must either be stable or be prepared by conventional rapid methods starting from stable ingredients. Such compositions consisted of a solution of a solution of conventional aqueous soluble infusion liquid, such as saline, glucose solution or a mixture of drinking water and glucose solution. However, compositions known to date have not been able to meet these criteria.

It is known that etomidate is only slightly soluble in neutral aqueous media and its solubility is increased in acidic media or in addition to organic solvents such as alcohol and chloroform. See Arzneimittel-forschung (Drug Research) 21, 1234 (1971). Two ethomidate-containing compositions are known in the literature that take advantage of acidic media and organic solvents.

The first composition described in Arzneimittel-Forschung (Drug Research) 21, 1234 (1971) is an etomidate-based solution in 60% water-soluble propylene glycol, which is used intravenously due to the very high concentration of cropyrenglycol. It cannot be allowed for injection. Some dilution occurs when the solution is diluted with the usual injection liquid, which is removed by stirring for a long time and the final concentration of etomidate in the solution is about 0.5 mg / ml or less. There is also some degree of trans esterification when etomidate is stored in propylene glycol.

Anaesthesology and Resuscitation 106

1. Another composition described in Berlin-Heidelberg-New York (1977) includes etomidate in phosphate buffer added with 4.2% glucose. This composition may be physiologically acceptable but ethomidate is extremely unstable as it is rapidly hydrolyzed in acidic media. Instant preparation of such compositions was not easy because it was necessary to dissolve very small amounts of etomidate sulfate in a large amount of buffer. Under these conditions it is very difficult to determine whether it is completely dissolved in the solid tax medium. It has also proved difficult to obtain etomidate sulfate in the absence of complete dust required for this form. Concentrated solutions of emidate sulfate in aqueous media that can be diluted with buffers are not feasible because they are not stable for these reasons.

The present invention relates to a process for the preparation of injectables containing ethomidate which is suitable for intravenous administration and which can be easily and quickly prepared by simply mixing two stable and uncomplicated solutions containing only a small amount of organic solvent.

In particular, the present invention provides the preparation of an injection solution containing etomidate for intravenous administration, which comprises a physiologically acceptable injection solution containing a concentrated solution of etomidate hydrochloride or hydrobromide in a medium containing at least 80% ethanol by weight. It is about a method.

Physiologically acceptable injectable solutions which can be used for this purpose are isotonic with blood, such as standard physiologically acceptable saline, glucose solutions and mixtures of saline and glucose solutions. Although hydrobromide salts of ethomidate can be tolerated, the use of hydrochloride salts is more preferred. In addition to ethomidate hydrochloride or hydrobromide, the medium may contain other solvents or materials that do not adversely affect the stability and efficiency of the composition.

It has been found that the medium can contain up to 20% by weight of water, although the presence of water increases the rate of hydrolysis of etomidate in the solution, which adversely affects the safety of the product. Lower concentrations of water in the medium, in particular below 5%, are suitable and in particular cases the content of water in the medium is below 0.5%. In most suitable examples the medium consisted of anhydrous ethanol.

The concentration of ethomidate in the composition for intravenous administration can vary within wide limits depending on the dosage required and the dosage required by the particular circumstances. It was found that an emidate concentration of 0.05-5 mg per ml was usually calculated by calculating the etomidate base content. The concentration of the medicament in the ethanol solution is generally 10 times higher than in the intravenous composition to induce the concentration of ethanol in the intravenous composition below the physiological limit.

The present invention will be described in more detail by the following examples without limitation.

Example 1

A. Preparation of Ethanol-Containing Applet of Ethomidate Hydrochloride with 250mg of Ethomidate Base Concentration per 2ml (Solution A)

While stirring, 143 g of etomidate (corresponding to 125 g base) is dissolved in anhydrous ethanol (99.8%) and the solution is filtered in the absence of dust on a 1.2 μm pore size filtrate. The solution is again sterilized by filtration on a membrane filter (hole of (0.2 μ)), filled in 2 ml of apple and sealed, and then autoclaved for 20 minutes at 120 ° C.

B. Preparation of Ethomidate-Containing Injections

Ethomidate containing injections containing 1 mg of etomidate base per ml are prepared by adding 2 ml of solution 4 to 250 ml of physiological saline or glucose solution.

The composition is suitable for intravenous administration to a patient.

Claims (1)

A method for the preparation of an injectable injection containing etomidate for intravenous administration, comprising adding a solution of etomidate hydrochloride or hydrobromide to a physiologically available injectable solution in a medium containing at least 80% ethanol.